Delivering alternating electric fields (e.g., TTFields) to a subject&#39;s spinal anatomy

ABSTRACT

This application discloses an improved approach for delivering alternating electric fields (e.g., TTFields) at a therapeutically effective strength to a target region of the spinal anatomy. In some embodiments, first and second sets of electrode elements are positioned with their centroids adjacent to upper and lower portions of the person&#39;s spine, respectively. In other embodiments, a first set of electrode elements is positioned with its centroid on an upper surface of the person&#39;s head, and a second set of electrode elements is positioned with its centroid adjacent to the person&#39;s spine (e.g., below the L3 vertebrae). Applying an AC voltage between the first and second sets of electrode elements generates a generally vertical field in the target region at levels that are not achievable using other layouts for positioning the electrode elements on the subject&#39;s body. These configurations are particularly useful for preventing and/or treating metastases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Applications62/750,315 (filed Oct. 25, 2018) and 62/781,358 (filed Dec. 18, 2018)each of which is incorporated herein by reference in its entirety.

BACKGROUND

TTFields are low intensity (e.g., 1-4 V/cm) alternating electric fieldswithin the intermediate frequency range (e.g., 100-300 kHz), which maybe used, for example, to treat tumors as described in U.S. Pat. No.7,565,205, which is incorporated herein by reference in its entirety.TTFields therapy is an approved mono-treatment for recurrentglioblastoma (GBM), and an approved combination therapy withchemotherapy for newly diagnosed GBM patients. TTFields can also be usedto treat tumors in other parts of a person's body (e.g. lungs, ovaries,pancreas). TTFields are induced non-invasively into the target region bytransducer arrays (i.e., arrays of capacitively coupled electrodeelements) placed directly on the patient's body (e.g., using theNovocure Optune™ system), and applying AC voltages between thetransducer arrays.

FIGS. 1 and 2 depict an example of a prior art layout for positioningthe transducer arrays on a patient's body for treating a tumor in thepatient's thorax and/or abdomen. In this layout, first and secondtransducer arrays are positioned on the front and back of the patient'sthorax and/or abdomen, respectively (as seen in FIG. 1); and third andfourth transducer arrays are positioned on the right and left sides ofthe patient's thorax and/or abdomen, respectively (as seen in FIG. 2).An AC voltage generator applies an AC voltage (e.g., 150 kHz) betweenthe front and back transducer arrays for a first interval of time (e.g.,one second), which generates an electric field with field lines thatgenerally run in a front/back direction. Then, the AC voltage generatorapplies an AC voltage at the same frequency between the right and lefttransducer arrays for a second interval of time (e.g., one second),which generates an electric field with field lines that generally run ina right/left direction. The system then repeats this two-step sequencefor the duration of the treatment.

SUMMARY OF THE INVENTION

One aspect of the invention is directed to a first method of applying analternating electric field to a target region in a person's spinalanatomy. The first method comprises affixing a first set of electrodeelements having a first centroid to the person's back with the firstcentroid positioned adjacent to an upper portion of the person's spine;and affixing a second set of electrode elements having a second centroidto the person's back with the second centroid positioned adjacent to alower portion of the person's spine. After affixing the first and secondsets of electrode elements, an alternating voltage is applied betweenthe first set of electrode elements and the second set of electrodeelements.

In some instances of the first method, the electrode elements of thefirst and second sets are capacitively coupled. In some instances of thefirst method, the alternating voltage that is applied between the firstset of electrode elements and the second set of electrode elements has afrequency between 100 kHz and 300 kHz. In some instances of the firstmethod, the first set of electrode elements comprises a plurality ofelectrode elements wired in parallel, and the second set of electrodeelements comprises a plurality of electrode elements wired in parallel.

In some instances of the first method, the first centroid is positionedat a height between the T8 and T9 vertebra, and the second centroid ispositioned at a height between the L3 and L4 vertebra. In some instancesof the first method, the first centroid is positioned at a height abovethe T1 vertebrae, and the second centroid is positioned at a heightbelow the L3 vertebrae.

In some instances of the first method, the alternating electric fieldhas a frequency and field strength that reduces viability of cancercells in the target region. In some instances of the first method, thealternating electric field has a frequency and field strength thatsuppresses an autoimmune response in the target region.

Another aspect of the invention is directed to a second method ofapplying an alternating electric field to a target region in a person'sspinal anatomy. The second method comprises affixing a first set ofelectrode elements having a first centroid to the person's head with thefirst centroid positioned on an upper surface of the person's head; andaffixing a second set of electrode elements having a second centroid tothe person's back with the second centroid positioned adjacent to theperson's spine. After affixing the first and second sets of electrodeelements, an alternating voltage is applied between the first set ofelectrode elements and the second set of electrode elements.

In some instances of the second method, the electrode elements of thefirst and second sets are capacitively coupled. In some instances of thesecond method, the alternating voltage that is applied between the firstset of electrode elements and the second set of electrode elements has afrequency between 100 kHz and 300 kHz. In some instances of the secondmethod, the first set of electrode elements comprises a plurality ofelectrode elements wired in parallel, and the second set of electrodeelements comprises a plurality of electrode elements wired in parallel.In some instances of the second method, the first centroid is positionedon the vertex of the head. In some instances of the second method, thesecond centroid is positioned at a height below the L3 vertebrae.

In some instances of the second method, the alternating electric fieldhas a frequency and field strength that reduces viability of cancercells in the target region. In some instances of the second method, thealternating electric field has a frequency and field strength thatsuppresses an autoimmune response in the target region.

Another aspect of the invention is directed to a third method ofdetermining where to position a first set of electrode elements having afirst centroid and a second set of electrode elements having a secondcentroid on a person's body before the first and second sets ofelectrode elements are used to apply an alternating electric field to atarget region in the person's spinal anatomy. The third method comprisesidentifying a location of a tumor in the person's spinal anatomy; andoutputting, based on the identified location, a recommendation forpositioning the first and second sets of electrode elements. Therecommendation is either (a) to affix the first set of electrodeelements to the person's back with the first centroid positionedadjacent to an upper portion of the person's spine, and to affix thesecond set of electrode elements with the second centroid positionedadjacent to a lower portion of the person's spine or (b) to affix thefirst set of electrode elements to the person's head with the firstcentroid positioned on an upper surface of the person's head, and toaffix the second set of electrode elements to the person's back with thesecond centroid positioned adjacent to the person's spine.

In some instances of the third method, the recommendation forpositioning the first and second sets of electrode elements is made by(a) simulating affixation of a first set of electrode elements to theperson's back at each of a first plurality of positions with the firstcentroid positioned adjacent to an upper portion of the person's spine,(b) simulating affixation of a second set of electrode elements to theperson's back at each of a second plurality of positions with the secondcentroid positioned adjacent to a lower portion of the person's spine,(c) simulating application of an alternating voltage between the firstset of electrode elements and the second set of electrode elements ateach of the first plurality of positions and at each of the secondplurality of positions, respectively, and (d) determining, based on step(c), which of the first plurality of positions and which of the secondplurality of positions results in an optimized alternating electricfield in the target region. In some of these instances, step (d)comprises determining which of the first plurality of positions andwhich of the second plurality of positions (i) maximizes a portion ofthe target region that has a field strength of at least 1 V/cm, (ii)maximizes uniformity of the field in the target region, or (iii)maximizes the intensity of the field in the target region.

In some instances of the third method, the recommendation forpositioning the first and second sets of electrode elements is made by(a) simulating affixation of a first set of electrode elements to theperson's head at each of a first plurality of positions with the firstcentroid positioned on an upper surface of the person's head, (b)simulating affixation of a second set of electrode elements to theperson's back at each of a second plurality of positions with the secondcentroid positioned adjacent to the person's spine, (c) simulatingapplication of an alternating voltage between the first set of electrodeelements and the second set of electrode elements at each of the firstplurality of positions and at each of the second plurality of positions,respectively, and (d) determining, based on step (c), which of the firstplurality of positions and which of the second plurality of positionsresults in an optimized alternating electric field in the target region.In some of these instances, step (d) comprises determining which of thefirst plurality of positions and which of the second plurality ofpositions (i) maximizes a portion of the target region that has a fieldstrength of at least 1 V/cm, (ii) maximizes uniformity of the field inthe target region, or (iii) maximizes the intensity of the field in thetarget region.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a prior art approach for positioning a pair of transducerarrays in front/back of a target region in a subject's thorax and/orabdomen to facilitate treatment with TTFields.

FIG. 2 depicts a prior art approach for positioning a pair of transducerarrays to the right/left of a target region in a subject's abdomen tofacilitate treatment with TTFields.

FIG. 3 depicts a first new approach for positioning transducer arrays ona subject's body, with one of the transducer arrays positioned above atarget region in the spinal anatomy and the other transducer arraypositioned below the target region in the spinal anatomy.

FIG. 4 depicts a rear view of a second new approach for positioningtransducer arrays on a subject's body, with one of the transducer arrayspositioned on an upper surface of the person's head and another one ofthe transducer arrays positioned adjacent to the person's spine.

FIGS. 5A and 5B depict rear and side views, respectively, of numericalsimulations for the transducer array layout shown in FIG. 4.

Various embodiments are described in detail below with reference to theaccompanying drawings, wherein like reference numerals represent likeelements.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Pre-clinical experiments suggest that in order for TTFields to exert atherapeutic effect, field intensities should exceed a threshold of about1 V/cm. And in the context of treating abdominopelvic cancers (e.g.pancreatic cancer and ovarian cancer), it is relatively easy to obtainthese field intensities by positioning a first pair of transducer arraysin front/back of the target region and a second pair of transducerarrays to the right/left of the target region, as depicted in FIGS. 1and 2, respectively. The location of the target region (which is theregion that is to receive the treatment e.g., to treat cancer or preventmetastases) is typically determined by the treating physician.

As used herein, “spinal anatomy” comprises the spinal cord, vertebrae,spinal discs, spinal nerves, and spinal cerebrospinal fluid.

Many types of cancer (e.g., breast, lung, and prostate) can metastasizeto the spinal anatomy. But until now, it was not possible to treat thesecancers using TTFields using the prior art layouts for positioning thetransducer arrays on a subject's body because the prior art layoutsyielded field intensities that were below the therapeutic threshold insignificant portions of the spinal anatomy (e.g., the spinal cord).

The inventors have recognized that the spinal anatomy, which has arelatively resistive bone structure that encapsulates a highlyconductive layer of fluid (i.e., cerebrospinal fluid), shunts thecurrent delivered across the body by the transducer arrays away fromportions of the spinal anatomy (e.g., the spinal cord), reducing thefield within it to below the therapeutic threshold. More specifically,numerical simulations show that when the epigastric layouts for thetransducer arrays depicted in FIG. 1 was used with a constant currentdensity of 200 mA (pk−pk) per disc at 150 kHz, the average fieldintensity within the spinal cord was only 0.52 V/cm. And when thelateral layouts for the transducer arrays depicted in FIG. 2 was usedwith the same current density at 150 kHz, the average field intensitywithin the spinal cord was only 0.26 V/cm. Both of these field strengthsare significantly lower than the recommended 1 V/cm.

FIG. 3 depicts a first new approach for positioning the transducerarrays on a person's body. More specifically, the transducer arrays arepositioned on the subject's back as shown in FIG. 3, with one of thetransducer arrays positioned above a target region in the spinal anatomyand the other transducer array positioned below the target region in thespinal anatomy. When the transducer arrays are positioned in this mannerand an AC voltage is applied between the upper and lower transducerarrays, provide field intensities above 1 V/cm can be achieved in thespinal cord.

In the exemplary embodiment depicted in FIG. 3, the upper transducerarray is positioned on the subject's back with its centroid locatedbetween the T8 and T9 vertebra, and the lower transducer array ispositioned on the subject's back with its centroid located between theL3 and L4 vertebra. The target region in the spinal anatomy lies betweenthose two centroids. With this configuration, part of the electriccurrent flows through the spinal anatomy, inducing a higher electricfield within the spinal cord and surrounding CSF. More specifically,numerical simulations for this transducer array layout reveal that whenan AC voltage is applied between the upper and lower transducer arrayswith a constant current density of 200 mA (pk−pk) per disc at 150 kHz,the average field intensity within the target region in the spinal cordwas 1.89 V/cm. This exceeds the values obtainable using the epigastricand lateral layouts by factors of 3.5× and 7×, respectively. Inaddition, using the FIG. 3 layout for the transducer array resulted inan average field intensity in the nerves that extend from the spinalcord of 1.64 V/cm.

A variation of the approach depicted in FIG. 3 may be used to treat theentire spinal cord and surrounding CSF by positioning the uppertransducer array at the neck (e.g. above the T1 vertebrae) andpositioning the lower transducer array near the bottom of the spine(e.g., below the L3 vertebrae).

FIG. 4 depicts a second new approach for positioning the transducerarrays on a person's body. More specifically, the transducer arrays arepositioned on the subject's body as shown in FIG. 4, with one of thetransducer arrays positioned centered on top of the subject's head andthe other transducer array positioned on the subject's back with itscentroid located below the L3 vertebra.

With this configuration, part of the electric current flows through thebrain and spinal anatomy, inducing a higher electric field within thespinal cord and surrounding CSF. The results of numerical simulationsfor this transducer array layout are depicted in FIGS. 5A and 5B forrear and side views, respectively. These results reveal that when an ACvoltage is applied between the upper and lower transducer arrays with aconstant current density of 200 mA (pk−pk) per disc, the mean fieldintensity in the spinal cord, nerves, and CSF was 1.37 V/cm, and themean field intensity in the CSF (taken alone) was 1.24 V/cm. Here again,these values dramatically exceed the values obtainable using theepigastric and lateral layouts described above in connection with FIGS.1 and 2, and also exceed the recommended 1 V/cm threshold.

The same construction for the transducer arrays that is used in otheranatomic locations may be used when the transducer arrays are positionednear the upper and lower portions of the spine in the FIG. 3 embodiment.Examples of conventional transducer arrays are the transducer arraysused with the Novocure Optune® system. These transducer arrays have aflexible backing that is configured for affixation to person's body.Suitable materials for the flexible backing include cloth, foam, andflexible plastic (e.g., similar to corresponding materials used inbandages). A plurality of capacitively coupled electrode elements arepositioned on the inner side of the flexible backing, and each of thecapacitively coupled electrode elements has a conductive plate with adielectric layer disposed thereon that faces inward. Optionally,temperature sensors (e.g., thermistors) may be positioned beneath eachof the electrode elements in a manner that is similar to theconventional arrangement used in the Novocure Optune® system.

A set of conductors connects to the conductive plates of each of theplurality of capacitively coupled electrode elements. The conductors maybe implemented using, for example, discrete wiring or using traces on aflex circuit. A layer of adhesive is configured to hold portions of theflexible backing that are not covered by any of the electrode elementsagainst the person's body.

Note that in the embodiments depicted in FIG. 3, each transducer arrayincludes 20 individual electrode element discs arranged in four rowswith 4 elements per row, and an additional two rows with 2 elements perrow. But in alternative embodiments, different layouts and/or adifferent number of individual electrode elements (e.g., between 4 and24) may be used. Examples include, but are not limited to, transducerarrays that each have 9 electrode elements using any suitable layout(e.g., arranged in three rows with 3 elements per row) and transducerarrays that each have 13 electrode elements using any suitable layout(e.g., arranged in three rows with 3 elements per row, plus anadditional two rows with 2 elements per row).

Similarly, in the embodiments depicted in FIG. 4, each transducer arrayincludes 13 individual electrode element discs arranged in three rowswith 3 elements per row, and an additional two rows with 2 elements perrow. But in alternative embodiments, a different number of individualelectrode elements (e.g., between 4 and 24) may be used.

After affixing the first and second sets of electrode elements asdescribed above, an alternating voltage is applied between the first setof electrode elements and the second set of electrode elements. In someembodiments, the frequency of the alternating voltage is between 100 kHzand 300 kHz. In some embodiments, the frequency of the alternatingvoltage is 150 kHz.

Advantageously, the layouts described herein can be used to deliveralternating electric fields at therapeutically effective levels (i.e.,greater than 1 V/cm) in portions of the spinal anatomy where thosetherapeutically effective levels were previously unobtainable. This canbe beneficial in a variety of contexts including treating existingtumors in portions of the spinal anatomy that were previouslyuntreatable, preventing metastases that may arise in portions of thespinal anatomy, and suppressing an autoimmune response in portions ofthe spinal anatomy.

The positions of each set of electrode elements may be varied from theexact locations depicted in the figures, as long as the movement issmall enough so that the respective anatomic description above remainsunchanged. For example, in the FIG. 3 embodiment, the upper set ofelectrode elements can move up, down, or to either side, as long as itscentroid is positioned on the person's back adjacent to an upper portionof the person's spine. Similarly, the lower set of electrode elementscan move up, down, or to either side, as long as its centroid ispositioned on the person's back adjacent to a lower portion of theperson's spine. In the FIG. 4/5 embodiment, the upper set of electrodeelements can move around on the person's head as long as the firstcentroid is positioned on an upper surface of the person's head; and thelower set of electrode elements can move around on the person's back aslong as the second centroid is positioned adjacent to the person'sspine.

Within this limited range of movement, the optimum position of each ofthe sets of electrode elements may be determined using simulations(e.g., finite element simulations) for each individual person tocalculate the resulting electric field for each combination of positionsfor the various sets of electrodes, and selecting the combination thatprovides the best results (e.g., a layout in which the largest portionof a target region has a field strength of at least 1 V/cm, a layoutwith the highest uniformity of the field in a target region, or a layoutthat maximizes the intensity of the field in a target region). Anindication of the selected combination is then output to the careprovider using, for example, a suitable display or printout. The careprovider will then apply the sets of electrode elements to the person atthe positions indicated by the output, hook the sets of electrodeelements up to an AC signal generator, and commence treatment.

A recommended position of each of the sets of electrode elements mayalso be generated without simulations by identifying a location of atumor in the person's spinal anatomy; and outputting, based on theidentified location (e.g., using a lookup table), a recommendation forpositioning the first and second sets of electrode elements. Therecommendation is either (a) to affix the first set of electrodeelements to the person's back with the first centroid positionedadjacent to an upper portion of the person's spine, and to affix thesecond set of electrode elements with the second centroid positionedadjacent to a lower portion of the person's spine (as depicted in FIG.3) or (b) to affix the first set of electrode elements to the person'shead with the first centroid positioned on an upper surface of theperson's head, and to affix the second set of electrode elements to theperson's back with the second centroid positioned adjacent to theperson's spine (as depicted in FIG. 4). An indication of the selectedcombination is then output to the care provider using, for example, asuitable display or printout. The care provider will then apply the setsof electrode elements to the person at the positions indicated by theoutput, hook the sets of electrode elements up to an AC signalgenerator, and commence treatment.

An additional aspect of the invention is directed to a firstcomputer-readable media upon which computer-executable instructions arestored. When the instructions are executed by a processor, the processorwill determine where to position a first set of electrode elementshaving a first centroid and a second set of electrode elements having asecond centroid on a person's body before the first and second sets ofelectrode elements are used to apply an alternating electric field to atarget region in the person's spinal anatomy. The processor willaccomplish this by identifying a location of a tumor in the person'sspinal anatomy; and outputting, based on the identified location, arecommendation for positioning the first and second sets of electrodeelements, wherein the recommendation is either (a) to affix the firstset of electrode elements to the person's back with the first centroidpositioned adjacent to an upper portion of the person's spine, and toaffix the second set of electrode elements with the second centroidpositioned adjacent to a lower portion of the person's spine or (b) toaffix the first set of electrode elements to the person's head with thefirst centroid positioned on an upper surface of the person's head, andto affix the second set of electrode elements to the person's back withthe second centroid positioned adjacent to the person's spine.

Optionally, when the computer-executable instructions stored on thefirst computer-readable media are executed by the processor, therecommendation that is made by the processor for positioning the firstand second sets of electrode elements is made by (a) simulatingaffixation of a first set of electrode elements to the person's back ateach of a first plurality of positions with the first centroidpositioned adjacent to an upper portion of the person's spine, (b)simulating affixation of a second set of electrode elements to theperson's back at each of a second plurality of positions with the secondcentroid positioned adjacent to a lower portion of the person's spine,(c) simulating application of an alternating voltage between the firstset of electrode elements and the second set of electrode elements ateach of the first plurality of positions and at each of the secondplurality of positions, respectively, and (d) determining, based on step(c), which of the first plurality of positions and which of the secondplurality of positions results in an optimized alternating electricfield in the target region. Optionally, in these embodiments, step (d)may comprise determining which of the first plurality of positions andwhich of the second plurality of positions (i) maximizes a portion ofthe target region that has a field strength of at least 1 V/cm, (ii)maximizes uniformity of the field in the target region, or (iii)maximizes the intensity of the field in the target region.

Optionally, when the computer-executable instructions stored on thefirst computer-readable media are executed by the processor, therecommendation that is made by the processor for positioning the firstand second sets of electrode elements is made by (a) simulatingaffixation of a first set of electrode elements to the person's head ateach of a first plurality of positions with the first centroidpositioned on an upper surface of the person's head, (b) simulatingaffixation of a second set of electrode elements to the person's back ateach of a second plurality of positions with the second centroidpositioned adjacent to the person's spine, (c) simulating application ofan alternating voltage between the first set of electrode elements andthe second set of electrode elements at each of the first plurality ofpositions and at each of the second plurality of positions,respectively, and (d) determining, based on step (c), which of the firstplurality of positions and which of the second plurality of positionsresults in an optimized alternating electric field in the target region.Optionally, in these embodiments, step (d) may comprise determiningwhich of the first plurality of positions and which of the secondplurality of positions (i) maximizes a portion of the target region thathas a field strength of at least 1 V/cm, (ii) maximizes uniformity ofthe field in the target region, or (iii) maximizes the intensity of thefield in the target region.

While the present invention has been disclosed with reference to certainembodiments, numerous modifications, alterations, and changes to thedescribed embodiments are possible without departing from the sphere andscope of the present invention, as defined in the appended claims.Accordingly, it is intended that the present invention not be limited tothe described embodiments, but that it has the full scope defined by thelanguage of the following claims, and equivalents thereof.

What is claimed is:
 1. A method of applying an alternating electricfield to a target region in a person's spinal anatomy, the methodcomprising: affixing a first set of electrode elements having a firstcentroid to the person's back with the first centroid positionedadjacent to an upper portion of the person's spine; affixing a secondset of electrode elements having a second centroid to the person's backwith the second centroid positioned adjacent to a lower portion of theperson's spine; and applying an alternating voltage between the firstset of electrode elements and the second set of electrode elements toimpose a tumor treating field in the target region in the person'sspinal anatomy, wherein the applying is performed after affixing thefirst and second sets of electrode elements.
 2. The method of claim 1,wherein the electrode elements of the first and second sets arecapacitively coupled.
 3. The method of claim 1, wherein the alternatingvoltage that is applied between the first set of electrode elements andthe second set of electrode elements has a frequency between 100 kHz and300 kHz.
 4. The method of claim 1, wherein the first set of electrodeelements comprises a plurality of electrode elements wired in parallel,and wherein the second set of electrode elements comprises a pluralityof electrode elements wired in parallel.
 5. The method of claim 1,wherein the first centroid is positioned at a height between the T8 andT9 vertebra, and wherein the second centroid is positioned at a heightbetween the L3 and L4 vertebra.
 6. The method of claim 1, wherein thefirst centroid is positioned at a height above the T1 vertebrae, andwherein the second centroid is positioned at a height below the L3vertebrae.
 7. The method of claim 1, wherein the alternating electricfield has a frequency and field strength that reduces viability ofcancer cells in the target region.
 8. The method of claim 1, wherein thealternating electric field has a frequency and field strength thatsuppresses an autoimmune response in the target region.